Gene Tie to Male Violence Is Studied

By NATALIE ANGIER,

Published: October 22, 1993

WASHINGTON, Oct. 21—
Scientists have identified a tiny genetic defect that appears to predispose some men toward aggression, impulsiveness and violence, a discovery that is likely to rekindle the harsh debate over the causes of criminal and abnormal behavior.

Researchers emphasized, however, that the finding was thus far limited to a single large family, and that the inherited illness was likely to be quite rare in the general population.

Nevertheless, scientists said the discovery counts as a persuasive advance for human behavioral genetics, a field that has lately been in disarray as previous announcements of genes for manic-depression, schizophrenia and alcoholism have either been disproved or come under withering criticism.

In the new work, researchers from the Netherlands and the United States studied a large Dutch family with a history of erratic and often hostile behavior among some, but not all, males in the group. Those afflicted often react to the most mildly stressful occasions with aggressive outbursts, shouting at, cursing or assaulting the person they deem a threat. Intelligence Found Low

At other times, the men have committed arson, attempted rape and exposed themselves in public. In addition, their intelligence is on the low end of normal, with an average I.Q. of around 85 to 90.

The researchers have linked the abnormal behaviors to mutations in the gene responsible for the body's production of monoamine oxidase-a, an enzyme critical for breaking down chemicals that allow brain cells to communicate. The scientists do not yet know the exact mechanism of the disorder, but they propose that lacking the metabolic enzyme, the brains of afflicted men end up with excess deposits of potent signaling molecules like serotonin, dopamine and noradrenaline. Those surplus neurotransmitters in turn stimulate erratic, often hostile conduct.

"A human behavior like aggression is very complex," said Dr. Han G. Brunner, a geneticist at University Hospital in Nigmegen, the Netherlands. "But our study shows that in certain instances a biological factor clearly influences the behavior." Dr. Brunner is the lead author of the new report, which is appearing Friday in the journal Science.

Comparing the monamine oxidase-a genes in 5 afflicted and 12 nonafflicted males of the family, the scientists found a difference in only a single biochemical building block among the thousands that make up the gene, a type of defect called a point mutation. In each case, those who showed a predisposition to aggressive, impulsive behavior had the mutation, and those who did not show such symptoms lacked it. Skin Cells Affected

Biochemical analysis of the men's skin cells also showed a severe deficiency in the essential enzyme.

"Other studies have implicated biological and inherited factors" in aggression, Dr. Brunner said. "This is the first that actually pinpoints a specific gene and a specific mutation within that gene."

The gene is located on the X chromosome, which explains why only males, with their single copy of the X chromosome, can suffer from the enzyme deficiency. Women can serve as carriers of the genetic defect, but are themselves protected from its symptoms by their possession of a second, good copy of the gene, sitting on their second X chromosome.

The researchers do not yet know how many people worldwide may suffer from the enzyme deficiency, but based on other types of hereditary disorders, they estimate that defects in monoamine oxidase-a are likely to afflict no more than 1 in 100,000 people. 'A Rare Disorder'

"What this paper does is give harder data to aggressive behavior in some people," said Dr. Emil F. Coccaro, director of clinical neuroscience research at the Medical College of Pennsylvania in Philadelphia. "But this is a rare disorder. It ain't the gene for all those people who are committing murder left and right."

Dr. Markku Linnoila, the scientific director of the National Institute on Alcohol Abuse and Alcoholism in Bethesda, Md., said: "This is an important step in understanding the biological determinants of human behavior. We learn by looking at extremes -- that's where the pay dirt is. Once you're able to make these kinds of findings, you look to see how it generalizes to the wider population."

Dr. Xandra O. Breakefield, an associate neurogeneticist at Massachusetts General Hospital in Charlestown and an author of the new report, cautions that even in a seemingly straightforward case like an enzyme disorder, the spectrum of the afflicted men's behaviors cannot be explained by a single genetic defect alone.

"Different members of the family behave differently," she said. "Some are functioning quite well, and one is married, has children and a job. Obviously how this syndrome is manifested as a behavior depends on many factors." She suggested that the finding could result in new therapies for the disorder, either drugs to help metabolize neurotransmitters, or a change in diet to prevent buildup of the chemicals. Criticism of 'Aggressive Genes'

Studies of the genetics of aggression and violence have fomented much acrimony among researchers and academics, some of whom see the research as disguised racism or attempts to reduce complex social and economic problems to a measurable blot on a laboratory X-ray. Last year a political uproar prompted the National Institutes of Health to cancel a conference scheduled to be held at the University of Maryland on the genetics of violence and criminal behavior.

Even Dr. Brunner emphasized that he and his colleagues had not set out to seek the genetic causes of aggression, but rather were responding to a request from a member of the Dutch family who already had done enough investigations on his own to conclude there was some hereditary abnormality at work in his bloodline.

Dr. Jonathan Beckwith, professor of microbiology and molecular genetics at Harvard Medical School in Boston and a critic of much research in behavioral genetics, complained that the latest study, like others before it, failed to define aggressive behavior in sufficient detail.

"It's been a long-term problem in this area, an insufficient characterization of the behaviors you're looking at," he said. "That's one reason why there have been so many announcements of genes that have later been retracted. There's often a lot less here than meets the eye."